Crystal Modifications of Odevixibat
The present invention relates to crystal modifications of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (odevixibat), more specifically crystal modifications 1 and 2 of odevixibat. The invention also relates to a process for the preparation of crystal modification 1 of odevixibat, to a pharmaceutical composition comprising crystal modification 1, and to the use of this crystal modification in the treatment of various conditions as described herein.
1 .- 27 . (canceled)
28 . A method for treating a cholestatic liver disease comprising orally administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical formulation comprising a crystalline hydrate of odevixibat, or a pharmaceutically acceptable salt thereof.
29 . The method of claim 28 , wherein the crystalline hydrate of odevixibat comprises from about 0 to about 2 moles of water associated with the crystal per mole of odevixibat.
30 . The method of claim 28 , wherein the crystalline hydrate of odevixibat is a sesquihydrate.
31 . The method of claim 28 , wherein the crystalline hydrate of odevixibat has an XRPD pattern, obtained with CuKα1-radiation, with peaks at ° 2θ positions 5.6±0.2, 6.7±0.2 and/or 12.1±0.2.
32 . The method of claim 31 , wherein the crystalline hydrate of odevixibat has an XRPD pattern, obtained with CuKα1-radiation, with specific peaks at ° 2θ positions 5.6±0.2, 6.7±0.2 and 12.1±0.2 and one or more of the characteristic peaks: 4.1±0.2, 4.6±0.2, 9.3±0.2, 9.4±0.2 and 10.7±0.2.
33 . The method of claim 28 , wherein the cholestatic liver disease is cholestatic pruritus.
34 . The method of claim 28 , wherein the cholestatic liver disease is selected from the group consisting of: biliary atresia, Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC).
35 . The method of claim 34 , wherein the cholestatic liver disease is biliary atresia.
36 . The method of claim 35 , wherein the biliary atresia is post-Kasai biliary atresia or post-liver transplantation biliary atresia.
37 . The method of claim 34 , wherein the cholestatic liver disease is PFIC.
38 . The method of claim 37 , wherein the PFIC is PFIC Type 1, PFIC Type 2, PFIC Type 3, non-specified PFIC, post-biliary diversion PFIC, or post-liver transplant PFIC.
39 . The method of claim 34 , wherein the cholestatic liver disease is ALGS.
40 . The method of claim 28 , wherein the subject is a pediatric subject.
41 . The method of claim 28 , wherein the subject is administered a daily dose of about 0.01 mg/kg to about 0.2 mg/kg of the crystalline hydrate of odevixibat, or a pharmaceutically acceptable salt thereof.
42 . The method of claim 28 , wherein the subject is administered a daily dose of about 0.2 mg to about 10 mg of the crystalline hydrate of odevixibat, or a pharmaceutically acceptable salt thereof.
43 . The method of claim 28 , wherein the subject is administered a daily dose of about 0.2 mg to about 5 mg of the crystalline hydrate of odevixibat, or a pharmaceutically acceptable salt thereof.
44 . The method of claim 28 , wherein the pharmaceutical formulation comprises a plurality of particles, each particle comprising a core and a coating layer surrounding the core, wherein the coating layer comprises the crystalline hydrate of odevixibat, or a pharmaceutically acceptable salt thereof.
45 . The method of claim 44 , wherein a unit dose of the pharmaceutical formulation comprises about 0.2 mg to about 5 mg of the crystalline hydrate of odevixibat, or a pharmaceutically acceptable salt thereof.
46 . The method of claim 44 , wherein a unit dose of the pharmaceutical formulation comprises about 0.2 mg to about 1.0 mg of the crystalline hydrate of odevixibat, or a pharmaceutically acceptable salt thereof.
47 . The method of claim 44 , wherein the core comprises microcrystalline cellulose.
48 . The method of claim 44 , wherein the coating layer further comprises a film-forming polymer.
49 . The method of claim 48 , wherein the film-forming polymer is hydroxypropyl methylcellulose.
50 . The method of claim 44 , wherein the plurality of particles is contained within a capsule.